1. Field of the Invention
The present invention belongs to the fields of pharmacology, medicine and medicinal chemistry and provides methods to treat psychotic conditions including schizophrenia and related conditions. In particular, this invention relates to the use of genomic analysis to determine a patient's responsiveness to antipsychotic medication including Iloperidone and methods to determine optimal treatment strategies.
2. Description of the Related Art
Ciliary Neurotrophic Factor (CNTF) was originally known as a survival factor for chick ciliary neurons in vitro but has more recently shown to be a survival factor for different neuronal cell types. CNTF is involved with the prevention of degeneration of motor axons and is a member of the interleukin-6 cytokine family. Barbin et al. used a survival assay for neurons from chick embryonic ciliary ganglia to report the neurotrophic activity of CNTF from chick eye. See, Barbin, G et al., J. Neurochem. 43:1468-1478, 1984. CNTF was also shown to have actions on sympathetic and sensory neurons in this study.
The CNTF gene also holds hope for the treatment of amyotrophic lateral sclerosis (ALS) and other similarly related disorders. In homozygous pmn/pmn mice a disorder occurs in which the hind limbs have a progressive motor neuropathy which becomes evident at the end of the third postnatal week. All the mice die six to seven weeks after birth from respiratory paralysis. Sendtner et al. treated the mice with CNTF and successfully improved motor function and reduced the morphologic symptoms of neural degeneration even when degenerative alterations were already present. See, Sendtner et al., Nature 358: 502-504, 1992.
Greater understanding was gained when CNTF gene expression was eliminated in mice by homologous recombination and the progressive atrophy and loss of motor neurons still took place, accompanied by a small reduction in muscle strength, see, Masu et al. Nature 365: 27-32, 1993. The authors of this study, stated that these results demonstrate that expression of the gene is not essential for the development of spinal motor neurons as determined by morphologic criteria, but that it is essential for maintenance of function in motor neurons in the postnatal period.
Takahashi et al. had similar findings in the lack of effects in the CNTF knockout mice. They found that roughly 2.5% of the Japanese population are homozygous for mutations that inactivate the CNTF gene, see, Takahashi et al. Nature Genet. 7: 79-84, 1994. Those that lack CNTF seem not to be adversely affected and have not shown any related neurologic defects.
CNTF receptor subunits share similar sequences with the leptin (LEP) receptor. Studies suggest that both CNTF and LEP cytokines have the ability to signal the hypothalamic satiety centers. These results came after systemic administration of CNTF and LEP to ob/ob mice, which led to rapid induction of the tis-11 primary response gene in the arcuate nucleus. When ob/ob mice, lacking a functional leptin, were treated with CNTF the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency were reduced. In contrast to leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack a functional leptin receptor, and in mice with diet-induced obesity, which are partially resistant to the actions of leptin.
CNTF protein is stored inside adult glial cells, perhaps awaiting release by some mechanism provoked by injury. It may not be essential for development and may, in fact, act in response to injury or some other type of stress. CNTF was characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord.
Polymorphism in the CNTF Gene
A polymorphism in the CNTF gene has been identified. The CNTF gene is located on 11q12.2 and the polymorphism is 103 G>A in GenBank sequence X55890 (Version 1) (see PubMed: 9285965). A mutation in an acceptor splice site caused the mRNA to splice incorrectly, thereby abolishing expression of the CNTF protein. The nucleotide change was a G to A transition at position −6 of the receptor splice site, leading to a frameshift from amino acid 39, resulting in a stop codon 24 amino acids downstream. The irregular mRNA was expected to code for a truncated protein 62 amino acids long (FS63 TER).
Analysis of tissue samples and transfection of CNTF minigenes into cultured cells demonstrated, that the mutated allele expressed only the mutated mRNA species. The homozygous mutant gene is not translated into protein as is shown by the finding that antibodies that recognise both the normal and mutated CNTF show complete lack of CNTF immunoreactivity in peripheral nerve tissue from a homozygous mutant subject. See, Takahashi et al. Nature Genet. 7: 79-84, 1994.
Psychotic Disorders
Psychoses exact a tremendous emotional and economic toll on the patients, their families, and society as a whole. Psychotic conditions, such as schizophrenia and related disorders (e.g. schizoaffective disorder), and including affective disorders (mood disorders) with psychotic symptoms (e.g. Bipolar Disorder) are complex and heterogeneous diseases of uncertain aetiology that afflict a large percentage of all populations world-wide.
Schizophrenia is characterised as having both “positive symptoms” (hallucinations, delusions, and conceptual disorganisation) and “negative symptoms” (apathy, social withdrawal, affect, and poverty of speech). Abnormal activity of the neurotransmitter dopamine is a hallmark of schizophrenia. Dopaminergic activity is reduced in the mesocortical system (resulting in negative symptoms) and is enhanced in the mesolimbic system (resulting in positive or psychotic symptoms). Several other neurotransmitters are involved, including serotonin, glutamate, and gamma-aminobutyric acid (GABA).
Antipsychotic drugs, in one form or another, have long been the basis of treatment of psychotic disorders. These drugs are sometimes used in combination with a mood regulating medication such as lithium or an antidepressant. For many years, schizophrenia was treated with classical antipsychotic drugs, the neuroleptics, that block central dopamine receptors. The neuroleptics are effective for treating the positive symptoms of schizophrenia, but have little or no effect on the negative symptoms. The ability of these drugs to antagonize dopamine receptors correlates with antipsychotic efficacy. Neuroleptic drugs include phenothiazines including aliphatics (e.g., chlorpromazine), piperidines (e.g., thioridazine), and piperazines (e.g., fluphenazine); butyrophenones (e.g., haloperidol); thioxanthenes (e.g., flupenthixol); oxoindoles (e.g., molindone); dibenzoxazepines (e.g., loxapine) and diphenylpiperidines (e.g., pimozide). Unfortunately, neuroleptics-resistant negative symptoms account for most of the social and vocational disability caused by schizophrenia. Further, neuroleptics cause extrapyramidal symptoms, including rigidity, tremor, bradykinesia (slow movement), and bradyphrenia (slow thought), as well as tardive dyskinesias and dystonias. For treatment of psychosis with medications, see, Textbook of Psychopharmacology, Schatzberg A F and Nemeroff C B, Editors, American Psychiatric Press. Wash. D.C. 1995.
Progress in the treatment of psychotic conditions has been achieved through the introduction of new, atypical antipsychotic agents. The side effect profile of these atypical antipsychotics is far superior to that of traditional agents. The atypical antipsychotics are a different class of antipsychotic drugs which have a different receptor binding profile and effectiveness against the symptoms of schizophrenia. The essential feature of an atypical antipsychotic is less acute extrapyramidal symptoms, especially dystonias, associated with therapy as compared to a typical antipsychotic such as haloperidol. Clozapine, the prototypical atypical antipsychotic, differs from the typical antipsychotics with the following characteristics: (1) greater efficacy in the treatment of overall psychopathology in patients with schizophrenia nonresponsive to typical antipsychotics; (2) greater efficacy in the treatment of negative symptoms of schizophrenia; and (3) less frequent and quantitatively smaller increases in serum prolactin concentrations associated with therapy (Beasley, et al., Neuropsychopharmacology, 14(2), 111-123, (1996)).
Atypical antipsychotics bind central serotonin2 (5-HT2) receptors in addition to D2 dopamine receptors. Unlike the neuroleptics, they improve negative as well as positive symptoms. They cause minimal extrapyramidal symptoms and rarely cause tardive dyskinesias, akathisia, or acute dystonic reactions. The first atypical antipsychotic drug approved for the treatment of schizophrenia was clozapine. Clozapine is effective for the treatment of schizophrenia, especially for subjects who do not respond to traditional neuroleptic therapy.
The treatment of psychotic disorders with antipsychotic agents has steadily improved over the years. However, up to now there has been no means, other than trial and error, to determine which patients will respond to an antipsychotic agent and what dose level a given patient may require to produce a therapeutic response without severe side effects. Since all antipsychotic agents, even the newer atypical ones, have significant side effects including extrapyramidal symptoms, such as rigidity, tremor, bradykinesia (slow movement), and bradyphrenia (slow thought), as well as tardive dyskinesias and dystonias this “trial and error” period could be time consuming, unpleasant and even dangerous for the patient and increased the likelihood of non-compliance. These side effects and toxic effects are dose dependent. Therefore there is a great need to develop means to determine whether or not a patient will respond to an antipsychotic agent and what dose range will be effective in a particular patient while minimising side effects.